3-Cyano-3-(3,4-disubstituted) phenylcyclohexyl-1-carboxylates

ABSTRACT

Novel 3-cyano-3-(3,4-disubstituted)phenylcyclohexyl-1-carboxylates or derivatives thereof and their corresponding cyclohexenyl analogs are described herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. These compounds are also useful mediating or inhibiting the enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in treating diseases in need of mediation or inhibition thereof.

FIELD OF INVENTION

The present invention relates to certain novel3-cyano-3-(3,4-disubstituted)phenylcyclohexyl-1-carboxylates and theircorresponding cyclohexenyl analogs, pharmaceutical compositionscontaining these compounds, and their use in treating allergic andinflammatory diseases and for inhibiting the production of TumorNecrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the “mediator approach” is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3′,5′-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺²-ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,“Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents” in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least tree types or strains of HIV havebeen identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIVinfection, T-cell-mediated immunity is impaired and infected individualsmanifest severe opportunistic infections and/or unusual neoplasms. HIVentry into the T lymphocyte requires T lymphocyte activation. Virusessuch as HIV-1 or HIV-2 infect T lymphocytes after T cell activation andsuch virus protein expression and/or replication is mediated ormaintained by such T cell activation. Once an activated T lymphocyte isinfected with HIV, the T lymphocyte must continue to be maintained in anactivated state to permit HIV gene expression and/or HIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells [See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214,1990].

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I), as shownbelow, useful in the mediation or inhibition of the enzymatic activity(or catalytic activity) of phosphodiesterase IV (PDE IV). The novelcompounds of Formula (I) also have Tumor Necrosis Factor (TNF)inhibitory activity.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I), as shownbelow.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (I).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (I). This method may be used for the prophylactictreatment or prevention of certain TNF mediated disease states amenablethereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (I).

The compounds of Formula (I) are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of Formula (I) are also useful in the treatment of yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of this invention are represented by Formula (I):

wherein:

R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R_(6, —(CR) ₄R₅)_(n)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties may be optionally substitutedwith one or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected from hydrogen or a C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetahydrofuranyl, furanyl tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranylC₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆;

X is YR₂, halogen, nitro, NR₄R₅, or formyl amine;

Y is O or S(O)_(m′);

m′ is 0, 1, or 2;

X₂ is O or NR₈;

X₃ is hydrogen or X;

X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈;

R₂ is independently —CH₃ or —CH₂CH₃ optionally substituted by 1 or morehalogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, —CH═CR_(8′)R_(8′), cyclopropyl optionally substituted byR_(8′), CN, OR₈, CH₂OR₈, NR₈R₁₀, CH₂NR₈R₁₀, C(Z′)H, C(O)OR₈, C(O)NR₈R₁₀,or C≡CR_(8′);

Z′ is O, NR₉, NOR₈, NCN, C(—CN)₂, CR₈CN, CR₈NO₂, CR₈C(O)OR₈,CR₈C(O)NR₈R₈, C(—CN)NO₂, C(—CN)C(O)OR₉, or C(—CN)C(O)NR₈R₈;

Z is C(Y′)R₁₄, C(O)OR₁₄, C(Y′)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-,4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]),(2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or5-imidazolidinyl); wherein all of the heterocyclic ring systems may beoptionally substituted one or more times by R₁₄;

Y′ is O or S;

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis optionally substituted one or more times by C₁₋₂ alkyl optionallysubstituted by one to three fluorines, —F, —Br, —Cl, —NO₂, —NR₁₀R₁₁,—C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —OC(O)R₈,—NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolylor tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl,piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R₈ is hydrogen or R₉;

R_(8′) is R₈ or fluorine;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together with thenitrogen form a 5 to 7 membered ring optionally containing at least oneadditional heteroatom which is O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining at least one additional heteroatom which is O, N, or S;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the novel compounds of Formula (I), and topharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable carrier or diluent. This invention alsorelates to a method of mediating or inhibiting the enzymatic (orcatalytic activity) of PDE IV in a mammal in need thereof and toinhibiting the production of TNF in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof Formula (I).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus, [Kidney Int., 37:362, 1990; Kidney Int., 35:494,1989] and central nervous system disorders such as depression andmulti-infarct dementia.

The compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by deceasedreplication, directly or indirectly, by the TNF inhibitors of Formula(1). Such viruses include, but are not limited to HIV-1, HIV-2 andHIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes groupof viruses, such as, but not limited to, Herpes zoster and Herpessimplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I).

The compounds of Formula (I) may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of Formula (I) are also useful in the treatment of yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The co-administration of the anti-fungal agent with a compound ofFormula (I) may be in any preferred composition for that compound suchas is well known to those skilled in the art, for instance the variousAmphotericin B formulations. Co-administration of an anti-fungal agentwith a compound of Formula (I) may mean simultaneous administration orin practice, separate administration of the agents to the mammal but ina consecutive manner. In particular, the compounds of Formula (I) may beco-administered with a formulation of Amphotericin B, notably forsystemic fungal infections. The preferred organism for treatment is theCandida organism. The compounds of Formula (I) may be co-administered ina similar manner with anti-viral or anti-bacterial agents.

The compounds of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)to a mammal in need of such treatment. Preferably, a compound of Formula(I) is administered for inhibiting or reducing the toxicity of theAmphotericin class of compounds, in particular Amphotericin B.

When R₁ for the compounds of Formula (I) is an alkyl substituted by 1 ormore halogens, the halogens are preferably fluorine and chlorine, morepreferably a C₁₋₄ alkyl substituted by 1 or more fluorines. Thepreferred halo-substituted alkyl chain length is one or two carbons, andmost preferred are the moieties —CF₃, —CH₂F, —CHF₂, —CF₂CHF₂, —CH₂CF₃,and —CH₂CHF₂. Preferred R₁ substitutents for the compounds of Formula(I) are CH₂-cyclopropyl, CH₂—C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl C₇₋₁₁polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl,benzyl or C₁₋₂ alkyl optionally substituted by 1 or more fluorines,—(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃, —(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and —(CH₂)₂₋₄OH.

When the R₁ term contains the moiety (CR₄R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄R₅)_(n) or (CR₄R₅)_(m); each repeatingmethylene unit is independent of the other, e.g., (CR₄R₅)_(n) wherein nis 2 can be -CH₂CH(—CH₃)—, for instance. The individual hydrogen atomsof the repeating methylene unit or the branching hydrocarbon canoptionally be substituted by fluorine independent of each other toyield, for instance, the preferred R₁ substitutions, as noted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0^(2,6)]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published Nov. 5, 1987, which disclosure is incorporatedherein by reference in its entirety.

Z is preferably C(O)R₈, C(O)OR₈, C(O)NR₈R₈, C(NR₈)NR₈R₈, CN, C(NOR₈)R₈,C(O)NR₈NR₈C(O)R₈, C(NCN)NR₈R₈, C(NCN)SR₉, (1-, 4- or5-{R₈}-2-imidazolyl), (1-, 4- or 5-{R₈}-3-pyrazolyl), (1-, 2- or5-{R₈}-4-triazolyl[1,2,3]), (1-, 2-, 4- or 5-{R₈}-3-triazolyl[1,2,4]),(1- or 2-{R₈}-5-tetrazolyl), (4- or 5-{R₈}-2-oxazolyl), (3- or4-{R₈}-5-isoxazolyl), (3-{R₈}-5-oxadiazolyl[1,2,4]),(5-{R₈}-3-oxadiazolyl[1,2,4]), (5-{R₈}-2-oxadiazolyl[1,3,4]),(5-{R₈}-2-thiadiazolyl[1,3,4]), (4- or 5-{R₈}-2-thiazolyl), (4- or5-{R₈}-2-oxazolidinyl), (4- or 5-{R₈}-2-thiazolidinyl),(1-, 4- or5-{R₈}-2-imidazolidinyl); most preferred are those compounds wherein theR₈ group of Z is R₄.

X₅ is preferably hydrogen, C₁₋₂ alkyl optionally substituted by one tothree fluorines, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, are C₁₋₂ alkyloptionally substituted by 1 or more halogens. The halogen atoms arepreferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a —CF₃,—CHF₂, or —CH₂CHF₂ moiety. Most preferred are the —CHF₂ and —CH₃moieties.

Preferred R₃ moieties are C(O)NH₂, C≡CR₈, CN, C(Z′)H, CH₂OH, CH₂F, CF₂H,and CF₃. More preferred are C≡CH and CN. Z′ is preferably O or NOR₈.

Preferred R₇ moieties include optionally substituted—(CH₂)₁₋₂(cyclopropyl), —(CH₂)₀₋₂(cyclobutyl), —(CH₂)₀₋₂(cyclopentyl),—(CH₂)₀₋₂(cyclohexyl), —(CH₂)₀₋₂(2-, 3- or 4-pyridyl),—(CH₂)₁₋₂(2-imidazolyl), —(CH₂)₂(4-morpholinyl), —(CH₂)₂(4-piperazinyl),—(CH₂)₁₋₂(2-thienyl), —(CH₂)₁₋₂(4-thiazolyl), and —(CH₂)₀₋₂phenyl;

Preferred rings when R₁₀ and R₁₁ in the moiety —NR₁₀R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom which is O, N,or S include, but are not limited to 1-imidazolyl, 2-(R₈)-1-imidazolyl,1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl, 2-triazolyl,5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl, 5-(R₈)-1-tetrazolyl,5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety —NR₁₀R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringoptionally containing at least one additional heteroatom which is O, N,or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but are not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-triazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl, or4-(R₁₄)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is optionally substituted by a heterocyclic ring suchas imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be optionally substituted by R₈ either onan available nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazoyl, or1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one ormore times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is—CH₂-cyclopropyl, —CH₂—C₅₋₆ cycloalkyl, —C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or —C₁₋₂ alkyloptionally substituted by 1 or more fluorines, and —(CH₂)₂₋₄ OH; R₂ ismethyl or fluoro-substituted alkyl, R₃ is CN or C≡CR₈; and X is YR₂.

Most preferred are those compounds wherein R₁ is —CH₂-cyclopropyl,cyclopentyl, methyl or CF₂H; R₃ is CN or C≡CH; X is YR₂; Y is oxygen; X₂is oxygen; X₃ is hydrogen; and R₂ is CF₂H or methyl. In most cases thecis configuration is preferred over the trans configuration. However,substituent pattern may influence the overall activity of thesecompounds in some manner which results in the trans configuration beingthe more active configuration. While the cis configuration is thought tobe more active in most instances, this must be confirmed on for eachcompound.

A preferred subgenus of the compounds of Formula (I) is the group ofcompounds of Formula (Ia)

wherein:

R₁ is CH₂-cyclopropyl, CH₂—C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl, C₇₋₁₁polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl,benzyl or C₁₋₂ alkyl optionally substituted by 1 or more fluorines,—(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃, —(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and —(CH₂)₂₋₄)OH;

X is YR₂, halogen, nitro, NR₄R₅, or formyl amine;

X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈;

Y is O or S(O)_(m′);

m′ is 0, 1, or 2;

R₂ is —CH₃ or —CH₂CH₃ optionally substituted by 1 or more halogens;

R₃ is hydrogen, C₁₋₄ alkyl, CH₂NHC(O)C(O)NH₂, halo-substituted C₁₋₄alkyl, CN, CH₂OR₈, C(Z′)H, C(O)OR₈, C(O)NR₈R₁₀, or C≡CR₈;

Z′ is O or NOR₈;

Z is C(O)R₁₄, C(O)OR₁₄, C(O)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄,C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (1-, 4- or5-{R₁₄}-2-imidazolyl), (1-, 4- or 5-{R₁₄}-3-pyrazolyl), (1-, 2- or5-{R₁₄}-4-triazolyl[1,2,3]), (1-, 2-, 4- or 5-{R₁₄}-3-triazolyl[1,2,4]),(1- or 2-{R₁₄}-5-tetrazolyl), (4- or 5-{R₁₄}-2-oxazolyl), (3- or4-{R₁₄}-5-isoxazolyl), (3-{R₁₄}-5-oxadiazolyl[1,2,4]),(5-{R₁₄}-3-oxadiazolyl[1,2,4]), (5-{R₁₄}-2-oxadiazolyl[1,3,4]),(5-{R₁₄}-2-thiadiazolyl[1,3,4]), (4- or 5-{R₁₄}-2-thiazolyl), (4- or5-{R₁₄}-2-oxazolidinyl), (4- or 5-{R₁₄}-2-thiazolidinyl), (1-, 4- or5-{R₁₄}-2-imidazolidinyl);

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis optionally substituted one or more times by C₁₋₂ alkyl optionallysubstituted by one to three fluorines, —F, —Br, —Cl, —NO₂, —NR₁₀R₁₁,—C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —OC(O)R₈,—NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl,or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃-C₇ cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl),piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), orphenyl;

R₈ is independently selected from hydrogen or R₉;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen or C₁₋₄ alkyl optionally substituted by one to threefluorines; or, when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom which is O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms which is O, N, or S;

provided that:

a) when R₁₂ is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN-morpholinyl, then q is not 1; or

or the pharmaceutically acceptable salts thereof.

Exemplified compounds of Formula (I) are:

methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;SB 212179

ethyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;SB

methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;SB 211572

methyl5-(3,4-bisdifluoromethoxyphenyl)-5-cyanocyclohex-1-ene-1-carboxylate; SB

methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];SB 210667

ethylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];SB 211600

methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];SB 212066

methylcis-[3-(3,4-bisdifluoromethoxyphenyl)-3-cyanocyclohexane-1-carboxylate];SB

cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; SB 210984

cis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; SB 212510

cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide];SB 211529

cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N-methylcarboxamide];SB 213021

cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N,N-dimethylcarboxamide];SB 212697

cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-{N-(4-bromobenzyl)carboxamide}];SB 212698

cis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];SB 214236

cis-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyano-cyclohexane];SB 212188

cis-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane]; SB213832

cis-{3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};SB 213826

cis-{3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]-oxadiazol-5-yl)cyclohexane};SB 214243

trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];SB 213677

trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];SB 213951

trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; SB 213731

trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; SB 213921

trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide];SB 213835

trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];SB 213921

trans-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyanocyclohexane];SB 213920

trans-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane]; andSB 214241,

trans-{3-cyano-3-(3-cyclopentyloxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclo-hexane};SB 214242

methyl3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;

methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;

3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,3-dicarbonitrile;and

5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,5-dicarbonitrile.

Some compounds of Formula (I) may exist in both racemic and opticallyactive forms; some may also exist in distinct diastereomeric formspossessing distinct physical and biological properties. All of thesecompounds are considered to be within the scope of the presentinvention. Therefore another aspect of the present invention is theadministration of either a racemate, a single enantiomeric form, asingle diastereomeric form, or mixtures thereof.

The terms cis and trans denote stereochemistry at the C-1 position ofthe cyclohexane ring relative to the R₃ group at the C-3 position.

The terms “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₆ alkyl” or “alkyl” includeboth straight or branched chain radicals of 1 to 10, unless the chainlength is limited thereto, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and thelike. “Alkenyl” includes both straight or branched chain radicals of 1to 6 carbon lengths, unless the chain length is limited thereto,including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl,or 3-methyl-2-propenyl. “Cycloalkyl” or “cycloalkyl alkyl” includesgroups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl,cyclopentyl, or cyclohexyl. “Aryl” or “aralkyl”, unless specifiedotherwise, means an aromatic ring or ring system of 6 to 10 carbonatoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably thearyl is monocyclic, i.e., phenyl. The alkyl chain includes both straightor branched chain radicals of 1 to 4 carbon atoms. “Heteroaryl” as usedherein, is meant an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxalyl, pyridyl, pyrimidyl,pyrazolyl, pyrrolyl, furanyl, or thienyl. “Halo” as used herein is meantall halogens, i.e., chloro, fluoro, bromo, or iodo.

The phrase “inhibiting the production of IL-1” or “inhibiting theproduction of TNF” means:

a) a decree of excessive in vivo IL-1 or TNF levels, respectively, in ahuman to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

“TNF mediated disease or disease states” means any and all diseasestates in which TNF plays a role, either by production of TNF itself, orby TNF causing another cytokine to be released, such as but not limitedto IL-1 or IL6. A disease state in which IL-1, for instance is a majorcomponent, and whose production or action, is exacerbated or secreted inresponse to TNF, would therefore be considered a disease state mediatedby TNF. As TNF-β (also known as lymphotoxin) has close structuralhomology with TNF-α (also known as cachectin), and since each inducessimilar biologic responses and binds to the same cellular receptor, bothTNF-α and TNF-β are inhibited by the compounds of the present inventionand thus are herein referred to collectively as “TNF” unlessspecifically delineated otherwise. Preferably TNF-α is inhibited.

“Cytokine” means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them. For instance, a monokine is generally referred to asbeing produced and secreted by a mononuclear cell, such as a macrophageand/or monocyte, but many other cells produce monokines, such as naturalkiller cells, fibroblasts, basophils, neutrophils, endothelial cells,brain astrocytes, bone marrow stromal cells, epidermal keratinocytes,and B-lymphocytes. Lymphokines are generally referred to as beingproduced by lymphocyte cells. Examples of cytokines for the presentinvention include, but are not limited to, Interleukin-1 (IL-1),Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha(TNF-α) and Tumor Necrosis Factor-beta (TNF-β).

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferably this cytokine is TNF-α.

All of the compounds of Formula (I) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) are useful in the method ofinhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

METHODS OF PREPARATION

Preparing compounds of Formula (I) can be carried out by one of skill inthe art according to the procedures outlined in the Examples, infra. Forexample, reactioning a compound of Formula (2)

wherein X or X₃ is other than Br, I, NO₂, amino, or S(O)_(m′)R₂ when m′is 0, 1 or 2, R₁ represents R₁ as defined in relation to Formula (I) ora group convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₃ represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an allyl, phenyl or benzyl group with,e.g., trifluoromethanesulfonic anhydride in the presence of a suitablebase, such as a hindered amine base, in a suitable solvent, such asdichloromethane, provides a compound of Formula (3)

wherein X or X₃ is other than Br, I, NO₂, amino, or S(O)_(m′)R₂ when m′is 0, 1 or 2, R₁ represents R₁ as defined in relation to Formula (I) ora group convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₃ represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an alkyl, phenyl or benzyl group.Palladium-catalyzed reduction of such a compound of Formula (3) undersuitable conditions then provides a compound of Formula (4)

a subset of the compounds of Formula (1) wherein X or X₃ is other thanBr, I, NO₂, amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2, the double bondis present, R₁ represents R₁ as defined in relation to Formula (I) or agroup convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₃ represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an alkyl, phenyl or benzyl group. Suchcompounds of Formula (1) wherein X or X₃ is other than Br, I, NO₂,amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2, the double bond is presentand Z is COOR₁₆ can be converted to other compounds of Formula (1)wherein X or X₃ is other than Br, I, NO₂, amino, or S(O)_(m′)R₂ when m′is 0, 1 or 2 and the double bond is present by standard procedures wellknown in the art [with proper manipulation (protection/deprotection) ofany chemically sensitive functional groups, if necessary] to thecorresponding ester, amide, nitrile, oxazolidinone, etc., Z groups ofFormula (I) wherein X or X₃ is other than Br, I, NO₂, amino, orS(O)_(m′)R₂ when m′ is 0, 1 or 2 and the double bond is present.Alternatively, such compounds of Formula (I) wherein X or X₃ is otherthan Br, I, NO₂, amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2, the doublebond is present, R₁ represents R₁ as defined in relation to Formula (I)or a group convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₃ represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an alkyl, phenyl or benzyl group may thenbe reduced by, e.g., catalytic hydrogenation, to compounds of Formula(I) wherein X or X₃ is other than Br, I, NO₂, amino, or S(O)_(m′)R₂ whenm′ is 0, 1 or 2 and the double bond is absent. Functional conversion ofthe Z group in such compounds of Formula (I) wherein X or X₃ is otherthan Br, I, NO₂, amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2, the doublebond is absent, R₁ represents R₁ as defined in relation to Formula (I)or a group convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₃ represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an alkyl, phenyl or benzyl group to other Zgroups can be accomplished by standard procedures well known in the art[with proper manipulation (protection/deprotection) of any chemicallysensitive functional groups, if necessary]. For example, preparation ofsome compounds of Formula (I) wherein R₃ is, e.g., C(═Z′)H proceed in ananalogous fashion from the compound of Formula (2) wherein ═Z′ is analdehyde protecting group, such as a dimethylacetal or a dioxolane,followed by aldehyde deprotection and subsequent manipulation bystandard procedures known to those of skill in the art to the remainingcompounds of Formula (I). Likewise, isomerization of compounds ofFormula (I) wherein X or X₃ is other than Br, I, NO₂, amino, orS(O)_(m′)R₂ when m′ is 0, 1 or 2, the double bond is absent, R₁represents R₁ as defined in relation to Formula (I) or a groupconvertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ as defined inrelation to Formula (I) or a group convertable to X, X₂ or X₃ and R₃represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and R₁₆ is an ally, phenyl or benzyl group and the R₃and Z groups are cis to the isomer wherein the R₃ and Z groups are transcan be accomplished either under kinetic or thermodynamic deprotonationconditions by standard procedures well known in the art with propermanipulation (protection/deprotection) of any chemically sensitivefunctional groups.

Alternatively, compounds of Formula (I) wherein X or X₃ is other thanBr, I, NO₂, amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2 may be preparedby a reaction sequence analogous to that described above but startingwith a compound of Formula (5)

wherein X or X₃ is other than Br, I, NO₂, amino, or S(O)m′ when m′ is 0,1 or 2, the double bond is absent, R₁ represents R₁ as defined inrelation to Formula (I) or a group convertable to R₁ and X, X₂ and X₃represent X, X₂ and X₃ as defined in relation to Formula (I) or a groupconvertable to X, X₂ or X₃ and R₃ represents R₃ as defined in relationto Formula (I) or a group convertable to R₃ and Z represents Z asdefined in relation to Formula (I) or a group convertable to Z.

Any remaining compounds of Formula (I) not described therein may beprepared by the analogous processes disclosed herein which comprise:

With proper manipulation (protection/deprotection) of any chemicallysensitive functional groups:

a) Compounds of Formula (I) wherein X or X₃ are formyl amine may beformed at the last step, by formylating a compound wherein X or X₃ isNH₂, obtained by removal of a protecting group from the aminefunctionality; such protective groups are well known to those skilled inthe art, See Greene, T. and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, 2nd Ed., John Wiley and Sons, New York (1991).

b) Compounds of Formula (I) wherein X or X₃ are Br, I or SR₂ may beprepared from a similarly deprotected amine by diazotization of theamine and diazonium displacement.

c) Compounds of Formula (I) wherein X or X₃ are NO₂ may be prepared froma similarly deprotected amine by oxidating the amine to the nitro group.

d) Compounds of Formula (I) wherein Y is S(O)m′ when m′ is 1 or 2 may beprepared from the compounds of Formula (I) wherein Y is S by firstprotecting any other oxidizable groups which are not to be oxidized thenoxidizing the SR₂ moiety under conditions well known those skilled inthe art and then deprotecting the previously protected group.

Compounds of Formulas (2) and (5) may be prepared in turn by theprocesses described in co-pending applications described in PCTapplications PCT/US93/02230, and its predecessor applicationsPCT/US93/02046, U.S. Ser. No. 07/968,806 filed Oct. 30, 1992 and U.S.Ser. No. 07/862,114 filed Apr. 2, 1992; and PCT applicationPCT/US93/10325 filed Mar. 12, 1993 and the predecessor cases from whichpriority is claimed therein.

Alternatively, reacting a compound of the Formula (6)

wherein R₁ represents R₁ as defined in relation to Formula (I) or agroup convertable to R₁ and X, X₂ and X₃ represent X, X₂ and X₃ asdefined in relation to Formula (I) or a group convertable to X, X₂ or X₃and R₂ and R₃ represent R₂ and R₃ as defined in relation to Formula (I)or a group convertable to R₂ or R₃ and wherein X or X₃ is other than Br,I, NO₂, amino, or S(O)_(m′)R₂ when m′ is 0, 1 or 2 and R₃ is other thanC(═Z′)H, with a suitable base in a suitable non-reacting solventfollowed by reaction with a suitable acylating agent, such as LS(O)₂CF₃,wherein L is a leaving group, to provide compounds of the Formula (7)

wherein Z is S(O)₂CF₃ and R₃ is other than C(═Z′)H. Metal catalyzedcarboxymethylation of such compounds of the Formula (7) then providesthe compounds of the Formula (I) wherein Z is COOR₁₆, which may beconverted to other compounds of the formula (1) as described above.Preparation of such compounds of Formula (I) wherein R₃ is C(═Z′)Hproceeds in an analogous fashion from the compound of Formula (6)wherein ═Z′ is an aldehyde protecting group, such as a dimethylacetal ora dioxolane, followed by deprotection to the aldehyde at the end of thereaction sequence and subsequent elaboration by standard proceduresknown to those of skill in the art to the remaining compounds of Formula(1) wherein Z′ is other than O.

Compounds of the Formula (6) may be prepared in turn by processesdescribed in co-pending application U.S. Ser. No. 08/130,215 filed Oct.1, 1993. P50199.

It will be recognized that compounds of Formula (I) may exist in twodistinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods.

The following examples and methods are provided to illustrate how themake and use the invention. These materials are not intended to limitthe invention in any manner, please refer to the claims appended heretofor determining what has been reserved to the inventors hereunder.

EXAMPLES Example 1 Preparation of methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,SB 212179

Route A

1a) Methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(trifluoromethylsulfonato)-cyclohex-1-ene-1-carboxylate

To a solution of 2,6-di-tert-butyl-4-methylpyridine (10.3 grams[hereinafter g], 50.2 millimoles [hereinafter mmol] andtrifluoromethanesulfonic anhydride (7.07 milliliters [hereinafter mL],41.8 mmol) in dichloromethane (165 mL) at room temperature under anargon atmosphere was added over 0.5 hours [hereinafter h] a solution of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one(12 g, 33.6 mmol) in dichloromethane (160 mL). The resulting mixture wasstirred overnight and then was concentrated to half-volume. Ether wasadded, the salt was removed by filtration and the filtrate wasconcentrated in vacuo. Purification by flash chromatography, elutingwith 3:1 hexanes/ethyl acetate, afforded a yellow oil (14.7 g, 89%). ¹HNMR (400 MHz, CDCl₃) δ7.0 (dd, J=8.5 and 2 Hz, 1H), 6.95 (d, J=2 Hz,1H), 6.90 (d, J=8.5 Hz, 1H), 3.85 (m, 8H), 3.10 (AB system, J=15 Hz,2H), 2.88 (m, 1H), 2.56 (m, 1H), 2.33 (m, 2H), 1.35 (m, 1H), 0.67 (dt,J=7 and 7 Hz, 2H), 0.49 (dt, J=7 and 7 Hz, 2H).

1b) Methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate

To a mixture of methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(trifluoromethylsulfonato)cyclohex-1-ene-1-carboxylate(0.34 g, 0.69 mmol), triphenylphosphine (7.2 mg, 0.03 mmol), palladiumacetate (3 mg, 0.013 mmol) and tributylamine (0.49 mL, 2.06 mmol) inN,N-dimethylformamide (1.5 mL) was added dropwise formic acid (0.054 mL,1.37 mmol). The resulting mixture was heated at 60° C. under an argonatmosphere for 1 h. The mixture was poured into 2 N hydrochloric acidand was extracted twice with ethyl acetate. The organic extract waswashed twice with 2 N hydrochloric acid, once with aqueous sodiumbicarbonate, once with brine and was evaporated. Purification by flashchromatography, eluting with 4:1 hexanes/ethyl acetate, provided an oil.Anal. (C₂₀H₂₃NO₄.3/4 H₂O) calcd: C, 67.68; H, 6.96; N, 3.95; found: C,67.50; H, 6.78; N 3.80.

Route B:

1c) 3-(3-Cyclopentyloxy-4-methoxyphenyl)cyclohex-2-en-1-one

n-Butyllithium (2.5M in hexanes, 15.5 mL, 38.9 mmol) was added dropwiseover 30 min to a solution of 3-cyclopentyloxy-4-methoxybromobenzene (10g, 37 mmol,) in dry tetrahydrofuran (100 mL) at −78° C. under an argonatmosphere. After 1.5 h. this solution was cannulated into a solution of3-methoxycyclohex-2-enone (4.62 g, 37.4 mmol, prepared as in Pearson, A.J.; Richards, I. C.; Gardner, D. V. J. Org. Chem. 1984, 49, 3887-3891)in dry tetrahydrofuran (50 mL) at 0° C. under an argon atmosphere. After2 h at room temperature, a mixture of ether and water was added, theaqueous layer was twice more extracted with ether, the combined extractwas washed with water and brine, was dried (magnesium sulfate) and wasevaporated. Trituration from ether/hexanes provided an off-white solid(7.33 g, 68%). Further purification of the mother liquor by flashchromatography, eluting with 1:3 ethyl acetate/hexanes, followed bytrituration from ether/hexanes, provided a white solid (1.59 g, 7%). mp89-90° C.; Anal. (C₁₈H₂₂O₃.1/8 H₂O) calcd: C, 74.91; H, 7.77; found: C,74.96; H, 7.76.

1d) 3-Cyano-3-(cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-2-en-1-one(1.46 g, 5.10 mmol) in dry toluene (45 mL) at room temperature under anargon atmosphere was added over 5 min diethylaluminumcyanide (1.0 Msolution in toluene, 15.5 mL, 15.5 mmol). After 6 h, the reaction wascarefully quenched with sodium hydroxide (2 N, 75 mL, 150 mmol), wasextracted three times with methylene chloride, the extract was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 1:4 ethyl acetate/hexanes, provided a paleyellow solid (1.20 g, 75%). mp 110-111° C.; Anal. (C₁₉H₂₃NO₃.1/8 H₂O)calcd: C, 72.30; H, 7.42; N, 4.44; found: C, 72.24; H, 7.45; N, 4.58.

1e) Methyl3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylateand methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate

A mixture of3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohex-1-en-1-yltrifluoromethanesulfonamide and5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-en-1-yltrifluoromethanesulfonamide (15.9 g, 35.7 mmol), triphenylphosphine(1.87 g, 7.14 mmol), palladium acetate (400 mg, 1.79 mmol) andtributylamine (25.5 mL, 107 mmol) in methanol (300 mL) was saturatedwith carbon monoxide, then stirred under a carbon monoxide balloon for 4days. The solvent was evaporated, the residue was diluted with water andwas extracted three times with dichloromethane, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatography,eluting with 85:15 hexanes/ethyl acetate, provided a white, waxy solid(6.21 g, 51%, R_(f)=0.36 (2:8 ethyl acetate:hexanes)). Also isolated wasthe isomer: methyl3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylateas a colorless oil (5.01 g, 39%, R_(f)=0.43 (2:8 ethylacetate:hexanes)).

1f) Methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

To a solution of methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohex-1-ene-1-carboxylate(6.21 g, 17.5 mmol) in methanol (50 mL) was added 10% palladium onactivated carbon (0.60 g) and the resulting mixture was hydrogenated at50 psi for 5 h. The mixture was filtered though a pad of Celite®, thesolid was washed with dichloromethane and the filtrate was concentratedunder reduced pressure. Purification by flash chromatography, elutingwith 85:15 hexanes:ethyl acetate, provided methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]as a colorless oil (5.60 g, 90%).

Alternatively, to a solution of methyl3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate(0.10 g, 0.28 mmol) in methanol (10 mL) was added 10% palladium onactivated carbon (0.05 g) and the resulting mixture was hydrogenated at50 psi for 6 h. The mixture was filtered through a pad of Celite®, thesolid was washed with dichloromethane and the filtrate was concentratedunder reduced pressure. Purification by flash chromatography, elutingwith 9:1 hexanes:ethyl acetate, provided methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]as a colorless oil (0.04 g, 43%). Also isolated was unreacted startingmaterial (0.04 g, 42%).

Example 2 Preparation of ethyl5cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,SB

Following the procedure of Example 1(a)-1(b), except substituting2-carboethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-onefor2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one,the title compound was prepared as an oil (0.57 g, 95%).

Example 3 Preparation of methyl5cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,SB 211572

Following the procedure of Example 1(a)-1(b), except substituting2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-onefor2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one,the title compound was prepared as a white solid (0.23 g, 54%). mp68-71° C.; Anal. (C₂₁H₂₅NO₄.1/2 H₂O) calcd: C, 69.40; H, 6.93; N, 3.85;found: C, 69.48; H, 7.33; N, 3.69.

Example 4 Preparation ofmethyl-5-(3,4-bisdifluoromethoxyphenyl)-5-cyanocyclohex-1-ene-1-carboxylate,SB

Following the procedure of Example 1(a)-1(b), except substituting2-carbomethoxy-4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-onefor2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one,the title compound was prepared (0.10 g, 51%). ¹H NMR (400 MHz, CDCl₃)δ7.41 (dd, J=8.5 and 2 Hz, 1H), 7.38 (d, J=2 Hz, 1H), 7.32 (d, J=8.5 Hz,1H), 7.17 (m, 1H), 6.56 (t, J=73 Hz, 1H), 6.55 (t, J=73 Hz, 1H), 3.78(s, 3H), 2.86 (AB system, J=18 Hz, 2H), 2.70 (m, 1H), 2.52 (m, 1H), 2.24(m, 1H), 2.04 (m, 1H).

Example 5 Preparation of methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate],SB 210667

To a solution of methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate(0.4 g, 1.17 mmol) in methanol (10 mL) was added 10% palladium onactivated carbon (0.15 g) and the resulting mixture was hydrogenated at50 psi for 3 h. The mixture was filtered through a pad of Celite®, thesolid was washed with dichloromethane and the filtrate was concentratedunder reduced pressure. Purification by flash chromatography, elutingwith 3:1 hexanes/ethyl acetate, provided a colorless oil (0.27 g, 67%).Anal. (C₂₀H₂₅NO₄) calcd: C, 69.95; H, 7.34; N, 4.08; found: C, 69.74; H,7.17; N, 4.06.

Example 6 Preparation of ethylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate],SB 211600

Following the procedure of Example 5, except substituting ethyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylatefor methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,the title compound was prepared (0.43 g, 75%). Anal. (C₂₁H₂₇NO₄.1/8 H₂O)calcd: C, 70.12; H, 7.64; N, 3.89; found: C, 70.11; H, 7.58; N, 4.23.

Example 7 Preparation of methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],SB 212066

Following the procedure of Example 5, except substituting methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylatefor methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,the title compound was prepared as a colorless oil (0.1 g, 67%). Anal.(C₂₁H₂₇NO₄.1/2 H₂O) calcd: C, 68.83; H, 7.70; N, 3.82; found: C, 68.83;H, 7.49; N, 3.63.

Example 8

Preparation of methylcis-[3-(3,4-bisdifluoromethoxyphenyl)-3-cyanocyclohexane-1-carboxylate,SB

Following the procedure of Example 5, except substituting methyl5-cyano-5-(3,4-bisdifluoromethoxyphenyl)cyclohex-1-ene-1-carboxylate formethyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate,the title compound was prepared.

Example 9 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] and separation of the 1R,3S- and 1S,3R-enantiomers, SB 210984

To a solution of methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.2 g, 0.58 mmol) in methanol (5.8 mL) under an argon atmosphere wasadded a solution of potassium hydroxide (0.098 g, 1.5 mmol) in water(3.4 mL). The resulting mixture was stirred at room temperatureovernight, then poured into acidic water and extracted three times withethyl acetate. The extract was dried (magnesium sulfate) andconcentrated under reduced pressure. Purification by flashchromatography, eluting with 5% methanol/chloroform, provided a foam(0.16 g, 84%). Anal. (C₁₉H₂₃NO₄.1/8H₂O) calcd: C, 68.81; H, 7.07; N,4.22; found: C, 68.81; H, 7.17; N, 4.26. Chiral separation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] was accomplished using preparative HPLC conditions with a 21.2×250mm Chiralpak AD column. The mobile phase of 85:15:0.2hexanes:isopropanol/water eluted at a flow rate of 10 mL/min withinjection of 0.1 g/10 mL at ambient temperature. Ultraviolet detectionof the eluting product was employed at 294 nm. Retention times were 26.3min for the 1R,3S-isomer and 34.2 min for the 1S,3R-isomer.

Example 10 Preparation ofcis-[3-cyano-3-(3-cyclopentyloxy)cyclohexane-1-carboxylic acid], SB212510

Following the procedure of Example 9, except substituting methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]for methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]and using a solvent mixture of 5:5:2 tetrahydrofuran/methanol/water, thetitle compound was prepared as a white solid (0.02 g, 78%). mp 48-50°C.; Anal. (C₂₀H₂₅NO₄.5/4 H₂O) calcd: C, 66.05; H, 7.55; N, 3.85; found:C, 65.98; H, 7.71; N, 4.21.

Example 11 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide]SB 211529

A solution ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] (0.1 g, 0.3 mmol) and N-methylmorpholine (0.04 mL, 0.36 mmol) in1,2-dimethoxyethane (3.2 mL) at room temperature under an argonatmosphere was treated with isobutyl chloroformate (0.045 mL 0.35 mmol).After 15 min. concentrated ammonium hydroxide (6 drops) was added andthe mixture was stirred for an additional 0.5 h. The mixture waspartitioned between dichloromethane and 5% aqueous sodium bicarbonate,was extracted three times, the organic extract was dried (potassiumcarbonate) and the solvent was evaporated. Purification by flashchromatography, eluting with 5% methanol/chloroform, provided a foam(0.05 g, 51%). This material was combined with the product of a reactionconducted on a similar scale and was rechromatographed. Anal.(C₁₉H₂₄N₂O₃.1/2H₂O) calcd: C, 67.63; H, 7.47; N, 8.30; found: C, 67.59;H, 7.28; N, 8.04.

Example 12 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N-methylcarboxamide]SB 213021

Following the procedure of Example 11, except substituting methylaminehydrochloride for ammonium hydroxide and using a four-fold excess ofN-methylmorpholine, the title compound was prepared as a foam. Anal.(C₂₀H₂₆N₂O₃.1/2H₂O) calcd: C, 68.35; H, 7.74; N, 7.97; found: C, 68.27;H, 7.70; N, 7.91.

Example 13 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N,N-dimethylcarboxamide]SB 212697

Following the procedure of Example 11, except substituting dimethylaminehydrochloride for ammonium hydroxide, the title compound was prepared asa white solid. mp 105° C.; Anal. (C₂₁H₂₈N₂O₃.1/4H₂O) calcd: C, 69.88; H,7.96; N, 7.76; found: C, 69.72; H, 7.78; N, 7.74.

Example 14 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-{N-(4-bromobenzyl)carboxamide}]SB 212698

Following the procedure of Example 11, except substituting 4-bromobenzylamine hydrochloride for ammonium hydroxide and using a four-fold excessof N-methylmorpholine, the title compound was prepared as a white solid.mp 162-163° C.; Anal (C₂₆H₂₉BrN₂O₃.1/2H₂O) calcd: C, 61.66; H, 5.97; N5.53; found: C, 61.66; H, 5.89; N, 5.57.

Example 15 Preparation ofcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]SB 214236

Following the procedure of Example 11, except substitutingcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid], the title compound was prepared as a white solid (0.6 g, 98%). mp145-146° C.; Anal. (C₂₀H₂₆N₂O₃.1/8H₂O) calcd: C, 69.69; H, 7.68; N,8.13; found: C, 69.53; H, 7.64; N, 8.03.

Example 16 Preparation ofcis-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyanocyclohexane] SB212188

A solution ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide](0.29 g, 0.87 mmol) and pyridine (0.15 mL, 1.86 mmol) in tetrahydrofuran(5 mL) at room temperature under an argon atmosphere was treated withtrifluoroacetic anhydride (0.13 mL, 0.92 mmol). After stirring for 2.5h, saturated aqueous ammonium chloride was added and the mixture waspartitioned between ethyl acetate and 10% hydrochloric acid. The aqueouslayer was extracted three times, the organic extract was dried(magnesium sulfate) and evaporated. Purification by flashchromatography, eluting with 2:1 hexanes/ethyl acetate, provided a solid(0.19 g, 71%). mp 138.5-139° C.; Anal. (C₁₉H₂₂N₂O₂) calcd: C, 73.52; H,7.14; N, 9.03; found: C, 73.63; H, 7.15; N, 8.84.

Example 17 Preparation ofcis-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane] SB213832

Following the procedure of Example 16, except substitutingcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide],the title compound was prepared as a white solid (0.18 g, 71%). mp113-115° C.; Anal. (C₂₀H₂₄N₂O₂) calcd: C, 74.05; H, 7.46; N, 8.63;found: C, 73.96; H, 7.42; N, 8.64.

Example 18 Preparation ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane]SB 213826

A solution ofcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide](0.097 g, 0.30 mmol) in N,N-dimethylacetamide dimethyl acetal (1.2 mL)was heated at 110° C. under an argon atmosphere for 1 h, was cooled andthe solvent was evaporated. Dioxane (1.2 mL), acetic acid (1.2 mL),hydroxylamine hydrochloride (0.03 g, 0.42 mmol) and 10% aqueous sodiumhydroxide (0.18 mL, 0.45 mmol) were added and the mixture was heated at90° C. under an argon atmosphere for 2 h. The mixture was cooled, waterwas added, the mixture was extracted three times with methylenechloride, the organic extract was dried (magnesium sulfate) and wasevaporated. Purification by flash chromatography, eluting with 35% ethylacetate/hexanes, provided an oil (0.06 g, 55%). Anal. (C₂₁H₂₅N₃O₃.1/4H₂O) calcd: C, 67.81; H, 6.91; N, 11.30; found: C, 67.73; H, 6.98; N,11.14.

Example 19 preparation ofcis-{3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]-oxadiazol-5-yl)cyclohexane}SB 214243

Following the procedure of Example 18, except substitutingcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide],the title compound was prepared as a colorless oil (0.29 g, 66%). Anal.(C₂₂H₂₇N₃O₃.1/2 H₂O) calcd: C, 67.67; H, 7.23; N, 10.76; found: C,67.72; H, 6.94; N, 10.52.

Example 20 Preparation of methyltrans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate],SB 213677

A solution of methyl cis[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.82 g, 2.39 mmol) in N-methylpyrrolidinone (10 mL) was treated withsodium cyanide (0.12 g, 2.51 mmol) and heated at 90° C. under an argonatmosphere for 6 h. The mixture was cooled, water (30 mL) was added, themixture was extracted once with ether, once with ethyl acetate, thecombined extract was washed with water, was dried (magnesium sulfate)and was evaporated. Purification by flash chromatography, eluting with3:1 hexanes/ethyl acetate, provided an oil (0.41 g, 50%). Anal.(C₂₀H₂₅NO₄.1/8H₂O) calcd: C, 69.49; H, 7.36; N, 4.05; found: C, 69.45;H, 7.20; N, 4.14.

Example 21 Preparation of methyltrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],SB 213951

Following the procedure of Example 20, except substituting methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]for methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate],the title compound was prepared (0.19 g, 40%). Anal. (C₂₁H₂₇NO₄.3/4 H₂O)calcd: C, 67.99; H, 7.74; N, 3.76; found: C, 68.07; H, 7.50; N, 4.09.

Example 22 Preparation oftrans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid], SB 213731

Following the procedure of Example 9, except substituting methyltrans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]for methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate],the title compound was prepared (0.17 g, 90%). Anal. (C₁₉H₂₂NO₄.Na)calcd: C, 64.95; H, 6.31; N, 3.99; found: C, 65.01; H, 6.51; N, 3.85.

Example 23 Preparation oftrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid], SB 213921

Following the procedure of Example 9, except substituting methyltrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]for methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]and using a solvent mixture of 5:5:2 tetrahydrofuran/methanol/water, thetitle compound was prepared (0.075 g, 84%). Anal. (C₂₀H₂₅NO₄.1/2 H₂O)calcd: C, 68.16; H, 7.44; N, 3.97; found: C, 67.84; H, 7.23; N, 4.13.

Example 24 Preparation oftrans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide]SB 213835

A solution oftrans[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] (0.19 g, 0.58 mmol) and triethylamine (0.10 mL, 0.70 mmol) indichloromethane (5.0 mL) at 0° C. under an argon atmosphere was treatedwith isobutyl chloroformate (0.083 mL, 0.70 mmol). After 10 min.,anhydrous ammonia was condensed into the reaction mixture and themixture was stirred for an additional 0.5 h while warming to roomtemperature. The mixture was partitioned between 95:5dichloromethane/methanol and 5% aqueous sodium carbonate, was extractedthree times, the organic extract was dried (magnesium sulfate) and thesolvent was evaporated. The residue was recrystallized from ethylacetate/hexanes to provide a white solid (0.14 g, 76%). mp 174-176° C.;Anal. (C₁₉H₂₄N₂O₃) calcd: C, 69.49; H, 7.37; N, 8.53; found: C, 69.19;H, 7.38; N, 8.59.

Example 25 Preparation oftrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]SB 213921

Following the procedure of Example 11, except substitutingtrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid], the title compound was prepared as a white solid (0.65 g, 95%).mp 150-151° C.; Anal. (C₂₀H₂₆N₂O₃) calcd: C, 70.15; H, 7.65; N, 8.18;found: C, 69.90; H, 7.66; N, 8.04.

Example 26 Preparation oftrans-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyanocyclohexane]SB 213920

Following the procedure of Example 16, except substitutingtrans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide]forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide],the title compound was prepared (0.10 g, 92%). Anal. (C₁₉H₂₂N₂O₂) calcd:C, 73.52; H, 7.16; N, 9.03; found: C, 73.34; H, 7.16; N, 9.02.

Example 27 Preparation oftrans-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane] SB214241

Following the procedure of Example 16, except substitutingtrans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide],the title compound was prepared as a white solid (0.16 g, 66%). mp118-119° C.; Anal. (C₂₀H₂₄N₂O₂.1/8 H₂O) calcd: C, 73.53; H, 7.48; N,8.58; found: C, 73.47; H, 7.44; N, 8.46.

Example 28 Preparation oftrans-{3-cyano-3-(3-cyclopentyloxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane}SB214242

Following the procedure of Example 18, except substitutingtrans-[3cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide]forcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide],the title compound was prepared as a colorless oil (0.21 g, 70%). Anal.(C₂₂H₂₇N₃O₃.3/2 H₂O) calcd: C, 64.69; H, 7.03; N, 10.29; found: C,64.98; H, 6.76; N, 9.90.

Example 29 Preparation of5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,5-dicarbonitrile

A suspension of3-cyano-3-(cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.63 g, 2.0mmol), 18-crown-6 (0.006 g, 0.1 mmol) and potassium cyanide (0.006 g,0.1 mmol) in dry toluene (2 mL) at room temperature under an argonatmosphere was treated dropwise with trimethylsilyl cyanide (0.32 mL,2.4 mmol) and the mixture was stirred for 2.5 h. Pyridine (4 mL) andphosphorous oxychloride (0.5 mL, 5.0 mmol) were added, and the solutionwas refluxed for 40 h. After quenching with ice, the reaction wasextracted three times with methylene chloride, the extract was washedwith sodium bicarbonate, 10% hydrochloric acid and water, was dried(magnesium sulfate) and the solvent was evaporated. Purification byflash chromatography, eluting with 1:4 ethyl acetate/hexanes, provided apale yellow oil (0.3 g, 42%). Anal. (C₂₀H₂₂N₂O₂.3/8H₂O) calcd: C, 72.98;H, 6.97; N, 8.51; found: C, 72.85; H, 6.80; N, 8.56; R_(f)=0.13 (4:1hexanes/ethyl acetate).

Example 30 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,3-dicarbonitrile

The title compound was isolated as the second product in Example 29 asan off-white solid (0.1 g, 19%). mp 77-79° C.; Anal. (C₂₀H₂₂N₂O₂.1/4H₂O)calcd: C, 73.48; H, 6.94; N, 8.57; found: C, 73.19; H, 6.74; N, 8.34;R_(f)=0.32 (4:1 hexanes/ethyl acetate).

Methods of Treatment

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals,it is normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition. The compounds of Formula (I)or a pharmaceutically acceptable salt thereof can be used in themanufacture of a medicament for the prophylactic or therapeutictreatment of any disease state in a human or other mammal which ismediated by inhibition of PDE IV, such as but not limited to asthmasallergic, or inflammatory diseases. The compounds of Formula (I) areadministered in an amount sufficient to treat such a disease in a humanor other mammal.

The method of treatment and monitoring for an HIV-infected humanmanifesting immune dysfunction or cytokine-mediated disease associatedproblems is taught in Hanna, WO 90/15534, Dec. 27, 1990. In general, aninitial treatment regimen can be copied from that known to be effectivein interfering with TNF activity for other TNF mediated disease statesby the compounds of Formula (I). Treated individuals will be regularlychecked for T cell numbers and T4/T8 ratios and/or measures of viremiasuch as levels of reverse transcriptase or viral proteins, and/or forprogression of monokine-mediated disease associated problems such ascachexia or muscle degeneration. If no effect is seen following thenormal treatment regimen, then the amount of the monokine activityinterfering agent administered is increased, e.g., by fifty percent perweek.

The pharmaceutical composition of the present invention will comprise aneffective, non-toxic amount of a compound of Formula (I) and apharmaceutically acceptable carrier or diluent. The compounds of Formula(I) are administered in conventional dosage forms prepared by combininga compound of Formula (I) in an amount sufficient to produce TNFproduction inhibiting activity, respectively, with standardpharmaceutical carriers according to conventional procedures. Theseprocedures may involve mixing, granulating, and compressing ordissolving the ingredients as appropriate to the desired preparation.

Thus, if a solid carrier is used, the preparation can be tableted,placed in a hard gelatin case in powder or pellet form, or in the formof a troche or lozenge. The amount of solid carrier will vary widely butpreferably will be from about 25 mg to about 1 gram. When a liquidcarrier is used, the preparation will be in the form of a syrup,emulsion, soft gelatin capsule, sterile injectable liquid such as anampule or nonaqueous liquid suspension. Where the composition is in theform of a capsule, any routine encapsulation is suitable, for exampleusing the aforementioned carriers in a hard gelatin capsule shell. Wherethe composition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates, or oils and are incorporated in a soft gelatin capsule shell.A syrup formulation will generally consist of a suspension or solutionof the compound or salt in a liquid carrier for example, ethanol,glycerine, or water with a flavoring or coloring agent.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit activity.

While it is possible for an active ingredient to be administered neat,it is preferable to present it as a pharmaceutical formulation. Theactive ingredient may comprise, for topical administration, from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of formulation, although itmay comprise as much as 10% w/w but preferably not in excess of 5% w/wand more preferably from 0.1% to 1% w/w of Formulation.

Formulations of the present invention comprise an active ingredienttogether with one or more acceptable carrier(s) thereof and optionallyany other therapeutic ingredient(s). The carrier(s) must be ‘acceptable’in the sense of being compatible with the other ingredients ofFormulation and not deleterious to the recipient thereof.

It will be recognized by one of skill in the art that the form andcharacter of the pharmaceutically acceptable carrier or diluent isdictated by the amount of active ingredient with which it is to becombined, the route of administration, and other well-known variables.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

Utility Examples Example A Inhibitory Effect of Compounds of Formula (I)on in vitro TNF Production by Human Monocytes

The inhibitory effect of compounds of Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

Example B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The exemplified compounds herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

Example C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called “Ia”), canine tracheaolis. PDEs Ia, Ib, Ic and IIIare partially purified using standard chromatographic techniques [Torphyand Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purifiedto kinetic homogeneity by the sequential use of anion-exchange followedby heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. PositiveIC₅₀'s in the nanomolar to μM range for compounds of the workingsexamples described herein for Formula (I) have been demonstrated.

Example D

The ability of selected PDE IV inhibitors to increase cAMP accumulationin intact tissues is assessed using U-937 cells, a human monocyte cellline that has been shown to contain a large amount of PDE IV. To assessthe activity of PDE IV inhibition in intact cells, nondifferentiatedU-937 cells (approximately 10⁵ cells/reaction tube) were incubated withvarious concentrations (0.01-1000 μM) of PDE inhibitors for one minuteand 1 μM prostaglandin E2 for an additional four minutes. Five minutesafter initiating the reaction, cells were lysed by the addition of 17.5%perchloric acid, the pH was neutralized by the addition of 1M potassiumcarbonate and cAMP content was assessed by RIA. A general protocol forthis assay is described in Brooker et al., Radioimmunassay of cyclic AMPand cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Thecompounds of the working examples as described herein for Formula (I)have demonstrated a positive EC₅₀s in the μM range in the above assay.

What is claimed is:
 1. A compound of Formula (I):

wherein: R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties may be optionally substitutedwith one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ andR₅ are independently selected from hydrogen or a C₁₋₂ alkyl; R₆ ishydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;provided that: a) when R₆ is hydroxyl, then m is 2; or b) when R₆ ishydroxyl, then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆; X is YR₂, halogen, nitro, NR₄R₅, or formylamine; Y is O or S(O)_(m′); m′ is 0, 1, or 2; X₂ is O or NR₈; X₃ ishydrogen or X; X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈; R₂ isindependently —CH₃ or —CH₂CH₃ optionally substituted by 1 or morehalogens; s is 0 to 4; R₃ is hydrogen, halogen, C₁₋₄ alkyl,CH₂NHC(O)C(O)NH₂, halo-substituted C₁₋₄ alkyl, —CH═CR_(8′)R_(8′),cyclopropyl optionally substituted by R_(8′), CN, OR₈, CH₂OR₈, NR₈R₁₀,CH₂NR₈R₁₀, C(Z′)H, C(O)OR₈, C(O)NR₈R₁₀, or C≡CR_(8′); Z′ is O, NR₉,NOR₈, NCN, C(—CN)₂, CR₈CN, CR₈NO₂, CR₈C(O)OR₈, CR₈C(O)NR₈R₈, C(—CN)NO₂,C(—CN)C(O)OR₉, or C(—CN)C(O)NR₈R₈; Z is C(Y′)R₁₄, C(O)OR₁₄,C(Y′)NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄, C(O)NR₈NR₈C(O)R₈,C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄, C(NR₁₄)NR₈R₈, C(NCN)NR₁₀R₁₄,C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]),(2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), (2-, 4- or5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl),or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocyclic ringsystems may be optionally substituted one or more times by R₁₄; Y′ is Oor S; R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, —F, —Br, —Cl, —NO₂,—NR₁₀R₁₁, —C(O)R₈, —C(O)OR₈, —OR₈, —CN, —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R₁₁,—OC(O)R₈, —NR₁₀C(O)NR₁₀R₁₁, —NR₁₀C(O)R₁₁, —NR₁₀C(O)OR₉, —NR₁₀C(O)R₁₃,—C(NR₁₀)NR₁₀R₁₁, —C(NCN)NR₁₀R₁₁, —C(NCN)SR₉, —NR₁₀C(NCN)SR₉,—NR₁₀C(NCN)NR₁₀R₁₁, —NR₁₀S(O)₂R₉, —S(O)_(m′)R₉, —NR₁₀C(O)C(O)NR₁₀R₁₁,—NR₁₀C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl,or tetrazolyl; q is 0, 1, or 2; R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl,triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2-or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R₈is hydrogen or R₉; R_(8′) is R₈ or fluorine; R₉ is C₁₋₄ alkyl optionallysubstituted by one to three fluorines; R₁₀ is OR₈ or R₁₁; R₁₁ ishydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together with thenitrogen form a 5 to 7 membered ring optionally containing at least oneadditional heteroatom which is O, N, or S; R₁₃ is oxazolidinyl,oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl,and each of these heterocyclic rings is connected through a carbon atomand each may be unsubstituted or substituted by one or two C₁₋₂ alkylgroups; R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ theymay together with the nitrogen form a 5 to 7 membered ring optionallycontaining at least one additional heteroatom which is O, N, or S;provided that: f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl,N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q isnot 1; or or the pharmaceutically acceptable salts thereof.
 2. Apharmaceutical composition comprising a compound of Formula (I)according to claim 1 and a pharmaceutically acceptable excipient.
 3. Amethod for treating an allergic or inflammatory state which methodcomprises administering to a subject in need thereof an effective amountof a compound of Formula (I) according to claim 1 alone or incombination with a pharmaceutically acceptable excipient.
 4. A compoundof claim 1 which is: methyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;ethyl5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;methyl5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;methyl5-cyano-5-(3,4-bisdifluoromethoxyphenyl)cyclohex-1-ene-1-carboxylate;methylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];ethylcis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];methylcis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];methylcis-[3-(3,4-bisdifluoromethoxyphenyl)-3-cyanocyclohexane-1-carboxylate];cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];cis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide];cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N-methylcarboxamide];cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-N,N-dimethylcarboxamide];cis-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-{N-(4-bromobenzyl)carboxamide}];cis-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];cis-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyano-cyclohexane];cis-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane];cis-{3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};cis-{3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-(3-methyl[1,2,4]-oxadiazol-5-yl)cyclohexane};trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylate];trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];trans-[3-cyano-3-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxamide];trans-[3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];trans-[3-(3-cyclopropylmethoxy-4-methoxyphenyl)-1,3-dicyanocyclohexane];trans-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,3-dicyanocyclohexane];trans-{3-cyano-3-(3-cyclopentyloxyphenyl)-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclo-hexane};3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,3-dicarbonitrile;or5-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1,5-dicarbonitrile.